2-(3,4-Dichlorophenyl)-4-(substituted amino)-quinazolines

ABSTRACT

A series of 2-(3,4-dichlorophenyl)-4-(substituted amino)quinazolines of the formula: ##STR1## wherein R is (1-pyrrolidinyl)propyl; 3-[bis-(2-hydroxyethyl)amino]propyl; 2,3-dihydroxypropyl; 3-diethylamino-2-hydroxypropyl; or 3-hydroxypropyl and various acid salts are effective antibacterial agents.

This invention is concerned with a series of2-(3,4-dichlorophenyl)-4-(substituted amino)quinazolines of the formula:##STR2## wherein R is (1-pyrrolidinyl)propyl;3-[bis-(2-hydroxyethyl)amino]propyl; 2,3-dihydroxypropyl;3-diethylamino-2-hydroxypropyl or 3-hydroxypropyl and various acid saltsthereof.

The members of this series of quinazolines are effective antimicrobialagents possessing in vitro antibacterial activity as exemplified in thetable herebelow:

    ______________________________________                                                        Minimum inhibitory                                                            Concentration in                                              Organism        mcg/ml                                                        ______________________________________                                        S. aureus       6.25 - 25                                                     S. fecalis      12.5 - 50                                                     Coryne. liq.     3.1 - 12.5                                                   ______________________________________                                    

The results set forth in the table above were secured in the commonlyused serial dilution technique for determining in vitro antibacterialeffects.

The antibacterial properties of those compounds, make them useful as anactive ingredient in various forms such as dusts, sprays, solutions,elixirs, unguents and the like to provide compositions designed tocombat bacterial growths.

The methods employed in the preparation of the members of the series ofthis invention are illustrated in the following examples in order thatthis invention may be fully available to and understood by those skilledin the art.

EXAMPLE I2-(3,4-Dichlorophenyl)-4-[3-(1-pyrrolidinyl)-propylamino]quinazolineDihydrochloride

To a solution of 4-chloro-2-(3,4-dichlorophenyl)quinazoline (37.0 g.,0.12 mole) in dimethylformamide (400.0 ml) was added N-(3-aminopropyl)pyrrolidine (31.0 g., 0.24 mole). After stirring and heating the mixturefor 4.0 hrs., the mixture was treated with charcoal and filtered. Thesolution was treated with H₂ O and then refrigerated. The cream coloredpowder removed by filtration was suspended in ethereal hydrochloric acidand treated with ethanol. After cooling, the off-white powder wasremoved by filtration and weighed 57.0 g., (100%). Tworecrystallizations from ethanol + HCl/CH₃ OH + HCl/Charcoal(precipitated with ether) provided an analytical sample melting at261°-263°. Anal. Calcd. for C₂₁ H₂₂ Cl₂ N₄.2HCl: C, 53.18; H, 5.10; N,11.81. Found: C, 52.96; H, 5.19; N, 11.67.

EXAMPLE II2-(3,4-Dichlorophenyl)-4-{3-[bis-(2-hydroxethyl)amino]propylamino}quinazoline

To a solution of 4-chloro-2-(3,4-dichlorophenyl)quinazoline (31.0 g.,0.1 mole) in dimethylformamide (500.0 ml) was addedN-(3-aminopropyl)-diethanolamine (32.0 g., 0.2 mole). The reactionmixture was stirred and heated for 5.0 hr., treated with charcoal, andfiltered while still hot. The solution was treated with H₂ O untilcloudy, then refrigerated. The off-white solid removed by filtration waswashed with ethanol and ethyl ether. After air drying, the productweighed 35.0 g., (83%). Recrystallization from CH₃ NO₂ /charcoalprovided an analytical sample melting at 102°-106°. Anal. Calcd. for C₂₁H₂₄ Cl₂ N₄ O₂ : C, 57.93; H, 5.55; N, 12.87. Found: C, 57.58; H, 5.91;N, 12.91.

EXAMPLE III2-(3,4-Dichlorophenyl)-4-(2,3-dihydroxypropylamino)quinazoline

A mixture of 46.5 g. (0.15 mole) of4-chloro-2-(3,4-dichlorophenyl)quinazoline in 500 ml ofdimethylformamide and 29 g (0.31 mole) of 2,3-dihydroxypropylamine washeated on a steam bath with stirring for 4 hrs. Diluted the mixture withwater until turbid and cooled in an ice bath. The colorless solid wasfiltered and recrystallized from methyl alcohol (Darco). The product wascollected as colorless needles melting at 155°-160° (with previoussoftening) in a yield of 49 g. (90%). Further recrystallization fromnitromethane gave 39 g. melting at 162°-164°. Anal. Calcd. for C₁₇ H₁₅Cl₂ N₃ O₂ : C, 56.06; H, 4.15; N, 11.54 Found: C, 55.63; H, 4.04; N,11.49.

EXAMPLE IV2-(3,4-Dichlorophenyl)-4-(3-diethylamino-2-hydroxypropylamino)quinazolineDihydrochloride Sesquihydrate

A mixture of 45 g. (0.145 mole) of4-chloro-2-(3,4-dichlorophenyl)quinazoline and 44 g. (0.3 mole) of1-amino-3-diethylamino-2-propanol in 500 ml of dimethylformamide wasstirred and heated on a steam bath for 4 hrs. The resulting mixture wasdiluted with 500 ml of water and was cooled to give 60 g. (95%) of thefree base.

This was suspended in ethanol and was saturated with anhydrous hydrogenchloride. The solution was cooled and was diluted with anhydrous ether.An oily material separated and the liquid was removed by decantation.The oily material was recrystallized from isopropanol to give 45 g.(60%) melting at 243°-245°.

Recrystallization from isopropanol lowered the melting point to202°-206°. Anal. Calcd. for C₂₁ H₂₄ Cl₂ N₄ O.2HCl.1-1/2 H₂ O: C, 48.57;H, 5.63; N, 10.79; Cl, 27.31; Found: C, 48.94; H, 5.34; N, 10.95; Cl,26.95

EXAMPLE V 2-(3,4-Dichlorophenyl)-4-(3-hydroxypropylamino)quinazoline

A mixture of 45 g. (0.145 mole) of4-chloro-2-(3,4-dichlorophenyl)quinazoline and 23 g. (0.31 mole) of3-hydroxypropylamine in 500 ml of dimethylformamide was heated on asteam bath for 4 hrs. The mixture was diluted with water and cooled andthe solid precipitate melting at 164°-166° was collected by filtrationin a yield of 50 g. (98%).

Recrystallization from methyl alcohol gave colorless needles melting at169°-170°. Anal. Calcd. for C₁₇ H₁₅ Cl₂ N₃ O: C, 58.63; H, 4.34; N,12.07 Found: C, 58.57; H, 4.34; N, 12.14.

What is claimed is:
 1. A compound of the formula: ##STR3## wherein R is(1-pyrrolidinyl)propyl; 3-[bis-(2-hydroxyethyl)amino]propyl;2,3-dihydroxypropyl; 3-diethylamino-2-hydroxypropyl; or 3-hydroxypropyland n is 0-1.
 2. The compound of claim 1 wherein R is(1-pyrrolidinyl)propyl and n is
 1. 3. The compound of claim 1 wherein Ris 3-[bis-(2-hydroxyethyl)amino]propyl and n is
 0. 4. The compound ofclaim 1 wherein R is 2,3-dihydroxypropyl and n is
 0. 5. The compound ofclaim 1 wherein R is 3-diethylamino-2-hydroxypropyl and n is
 1. 6. Thecompound of claim 1 wherein R is 3-hydroxypropyl and n is 0.